Insights into Mechanisms of Cisplatin Resistance and Potential for Its Clinical Reversal

Cisplatin in combination with other cytotoxic agents is the backbone for a potential cure of testicular germ cell neoplasms and is a critical factor in the substantial activity observed in the treatment of small cell lung cancer, bladder cancer, and ovarian germ cell tumors. Resistance to cisplatin at the onset of treatment or at relapse limits its curative potential, however. Laboratory studies using both cells selected for cisplatin resistance by exposure to sublethal concentrations and biopsy specimens from patients' tumors provide insights for the potential mechanisms of resistance. The mechanisms identified in vitro include a complex and wide array of related and unrelated pathways such as alterations in cellular drug transport, enhanced DNA repair dependent and independent of signal transduction pathways, and enhanced intracellular detoxification such as glutathione and metallothionein systems. Studies of these mechanisms have identified a number of agents with known potential for administration to humans and that reverse cisplatin resistance in vitro; for example, reversal of cellular accumulation defects by dipyridamole; inhibition of DNA repair by hydroxyurea, pentoxifylline, and novobiocin; inhibition of the glutathione system by ethacrynic acid and buthionine sulfoximine; and inhibition of signal transduction pathways by cyclosporine, tamoxifen, and calcium channel-blocking agents. Current phase I clinical trials are focusing on the most effective doses and schedules to administer these agents in combination with cisplatin. Initial uncontrolled trials in limited numbers of patients suggest that the addition of modulators of cisplatin has the potential to reverse resistance in patients previously failing therapy. Another promising avenue for circumventing cisplatin resistance is the development of noncross-resistant platinum analogs.     

Pseudomonas aeruginosa elastase stimulates ERK signaling pathway and enhances IL- 8 production by alveolar epithelial cells in culture

OBJECTIVE AND DESIGN: Bacterial products as well as the host airway inflammatory responses contribute to the pathogenesis of Pseudomonas infections. We sought to determine if Pseudomonas elastase (PE) induces mitogen-activated protein (MAP) kinase activity in association with interleukin-8 (IL-8) production by alveolar epithelial cells. METHODS: We utilized Western blot analysis to detect phosphorylation of signaling intermediates and ELISA was used to measure IL-8 production. RESULTS: We found that PE induces phosphorylation of the extracellular signal-regulated (ERK1/2) proteins of the MAPK pathway in A549 epithelial cells. Similar results were obtained using primary cultures of rabbit alveolar type II epithelial cells. PE also enhanced IL-8 production, which was abolished in the presence of the ERK activation inhibitor U0126. CONCLUSIONS: We conclude that PE activates the ERK1/2 arm of the MAPK pathway and that activation of this pathway results in enhanced IL-8 production. The results demonstrate that PE may augment pulmonary inflammation via cellular signaling that regulates expression of IL-8.     

The incidence of Hill-Sachs lesions in initial anterior shoulder dislocations

We undertook a prospective study using arthroscopy to determine the intraarticular derangement caused by initial anterior shoulder dislocations. Of our 32 patients, 15 (47%) had a grade I, grade II, or grade III Hill-Sachs lesion. The patients were 29 men and 3 women whose ages ranged from 15 to 28 years (mean 22 years). All of the patients studied were United States military personnel or members of their families. None of the patients had had prior injuries of the affected shoulder, and all underwent arthroscopy within 72 h of injury. Few reports describe a Hill-Sachs lesion in a patient following a single anterior dislocation. Early reports of this lesion were based on indirect (radiographic) evidence. Our arthroscopic findings indicate that the incidence of this lesion after one anterior dislocation is higher than previously thought.     

Factors That Influence Women's Decisions About Whether to Participate in Research: An Exploratory Study

Abstract: Background : Women are increasingly being asked to consider participating in medical research. We sought to investigate views of women who participated in and declined to participate in a study that was part of a program of maternity care research. Methods : An exploratory study using focus group interviews and semistructured interviews was conducted. A purposive sample of 17 postnatal women who had participated in research, from a hospital in the North West of England, were interviewed. An open coding mechanism to identify emergent themes was used for the analysis of data. Results : Of women who had not declined to participate in any research, the following themes were identified: altruism versus self‐protection, enhanced versus inferior care, professional guidance versus self‐direction, and welcome versus unacceptable methodology. Of women who had participated in some research but declined to participate in other research, the following themes were identified: feeling disempowered by the process, inability to believe equipoise existed, and practical inconvenience. Conclusions : These findings suggest that although health care researchers adopt an individualistic approach to care, they may fail to adopt a similar approach within research. What is important and acceptable to women needs to be ascertained to develop appropriate research strategies. This plan will ensure that research is carried out to the highest ethical standard, which may increase recruitment rates.     

Characterization of hindlimb motoneuron membrane properties in acute and chronic spinal cats

The purpose of this study was to determine if changes in hindlimb motoneuron membrane electrical properties occur 4–6 months after spinal transection in the adult animal. Eight acute and nine chronic animals were spinalized at T₁₂. Intracellular recordings from motoneurons innervating the triceps surae were performed. Membrane electrical properties, including resting potential, action potential peak amplitude, afterhyperpolarization duration, rheobasic current, input resistance and axonal conduction velocity were measured. There were no statistical differences found between group means or frequency distributions in the membrane properties of motoneurons assessed from acute and chronic spinal animals. Thus, alteration of motoneuron membrane properties does not appear to be a major contributing factor to the hyperexcitable hindlimb reflex activity demonstrated by chronic spinal animals.     

Serous retinal detachment — an unusual complication of preeclampsia

A case of preeclampsia complicated by serous retinal detachment is described. The anaesthetic implications are discussed.     

L-2-oxothiazolidine-4-carboxylate as a cysteine precursor: efficacy for growth and hepatic glutathione synthesis in chicks and rats

Chick and rat experiments were conducted to determine the efficacy of L-2-oxothiazolidine-4-carboxylate (OTC) as a cysteine (Cys) precursor for growth and hepatic glutathione (GSH) biosynthesis. Isosulfurous graded increments of OTC and Cys were added to Cys-free purified amino acid diets that were adequate in methionine. Curvilinear responses to both Cys and OTC for chicks and rats were obtained. Hepatic GSH accumulated in chicks only at dietary Cys levels above 0.10%. In rats, hepatic GSH increased linearly as dietary Cys content increased from deficient to adequate and from adequate to excessive. Utilization of OTC by chicks was as efficacious as isosulfurous levels of Cys for growth and hepatic GSH biosynthesis. In rats, OTC was slightly inferior to Cys for growth and hepatic GSH biosynthesis. Exponential regression slope-ratio growth efficacy values for OTC were 78.5% for chicks and 70.2% for rats; multiple linear regression slope-ratio GSH biosynthesis efficacy values were 80.3% for chicks and 83.7% for rats. It is concluded that orally administered OTC is active as a Cys precursor.